Relationships between circadian ehythms in response to drugs and in hepatic microsomal drug metabolism will be investigated. It will be determined if circadian rhythms in the duration of response of drugs such as hexobarbital, zoxazolamine, tremorine, amphetamine and meperidine in the rat are the result of rhythmic variation in drug metabolism. in tissue sensitivity to these drugs, or both. Associations between rhythms in drug action and drug metabolism will be investigated under conditions of normal and reversed lighting, constant illumination, endocrine ablations, corticoster-one treatment and phenobarbital treatment. Circadian periodicity in "tissue sensitivity" to certain of these drugs will be examined by measuring plasma and brain concentrations of drugs at termination of the pharmacological response, by dose-response analysis, and by a more direct electroencephalographic measure of central nervous system sensitivity to depressants. Experiments will also be undertaken to assess to possibility that circadian rhythms in drug metabolism are a refection of similar rhythms in plasma corticosterone concentration in the rate.